Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transgenic mouse models expressing mutant superoxide dismutase 1 (SOD1) have been critical in furthering our understanding of amyotrophic lateral sclerosis (ALS). However, such models generally overexpress the mutant protein, which may give rise to phenotypes not directly relevant to the disorder. Here, we have analysed a novel mouse model that has a point mutation in the endogenous mouse Sod1 gene; this mutation is identical to a pathological change in human familial ALS (fALS) which results in a D83G change in SOD1 protein. Homozgous Sod1(D83G/D83G) mice develop progressive degeneration of lower (LMN) and upper motor neurons, likely due to the same unknown toxic gain of function as occurs in human fALS cases, but intriguingly LMN cell death appears to stop in early adulthood and the mice do not become paralyzed. The D83 residue coordinates zinc binding, and the D83G mutation results in loss of dismutase activity and SOD1 protein instability. As a result, Sod1(D83G/D83G) mice also phenocopy the distal axonopathy and hepatocellular carcinoma found in Sod1 null mice (Sod1(-/-)). These unique mice allow us to further our understanding of ALS by separating the central motor neuron body degeneration and the peripheral effects from a fALS mutation expressed at endogenous levels.
...
PMID:A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity. 2546 78

Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects upper (UMN) and lower motor (LMN) neurons. It is associated with a short survival and there is no effective treatment, in spite of a large number of clinical trials. Strong efforts have been made to identify novel disease biomarkers to support diagnosis, provide information on prognosis, to measure disease progression in trials and increase our knowledge on disease pathogenesis. Electromyography by testing the function of the LMN can be used as a biomarker of its dysfunction. A number of electrophysiological and neuroimaging methods have been explored to identify a reliable marker of UMN degeneration. Recently, strong evidence from independent groups, large cohorts of patients and multicenter studies indicate that neurofilaments are very promising diagnostic biomarkers, in particular cerebrospinal fluid and blood levels of phosphoneurofilament heavy chain and neurofilament light chain. Furthermore, their increased levels are associated with poor prognosis. Additional studies have been performed aiming to identify other biomarkers, which alone or in combination with neurofilaments could increase the sensitivity and the specificity of the assays. Emerging molecular marker targets are being discovered, but more studies with standardized methods are required in larger cohorts of ALS patients.
...
PMID:Emerging molecular biomarker targets for amyotrophic lateral sclerosis. 2677 96

Motor or motor-predominant neuropathies may arise from disease processes affecting the motor axon and/or its surrounding myelin. Lower motor neuron syndrome (LMNS) arises from a disease process affecting the spinal motor neuron itself. The term LMNS is more generally used, rather than motor neuronopathy, although both entities are clinically similar. Common features are muscle weakness (distal or proximal) with atrophy and hyporeflexia, but no sensory involvement. They can be acquired or hereditary. Immune-mediated neuropathies (multifocal motor neuropathy, motor-predominant chronic inflammatory demyelinating polyneuropathy) are important to identify, as effective treatments are available. Other acquired neuropathies, such as infectious, paraneoplastic and radiation-induced neuropathies are also well known. Focal LMNS is an amyotrophic lateral sclerosis (ALS)-mimicking syndrome especially affecting young adults. The main hereditary LMNSs in adulthood are Kennedy's disease, late-onset spinal muscular atrophy and distal hereditary motor neuropathies. Motor neuropathies and LMNS are all clinical entities that should be better known, despite being rare diseases. They can sometimes be difficult to differentially diagnose from other diseases, particularly from the more frequent ALS in its pure LMN form. Nevertheless, correct identification of these syndromes is important because their treatment and prognoses are definitely different.
 ...
PMID:Motor neuropathies and lower motor neuron syndromes. 2843 7

Rationale. In recent years, significant advances have been made on the subject of MRI examination techniques, which have opened new avenues of research regarding the spinal involvement in amyotrophic lateral sclerosis (ALS). Objective. Our objective was to compile and analyze the available literature data, concerning the MRI of the cervical spine in ALS, detailing the metrics and their significance in diagnosis and follow-up. Methods and results. We have conducted an extensive search on the subject using literature data published over the last fifteen years, correlating it with our own experience. In ALS, there is a permanent interest in developing new biomarkers that might be sensitive to spatial and temporal patterns of neurodegeneration, which will permit early diagnosis and hopefully lead to new therapeutic approaches. Both diffusion tensor imaging (DTI) and spinal cord morphometry (especially spinal atrophy) reflect different aspects of the disease and correlate with clinical deterioration. Newer approaches like inhomogeneous magnetization transfer (ihMTR) and multiparametric analysis seem to have better sensitivity, are more appropriate for follow-up, and lend themselves to prognostic conclusions. Discussion. We conclude that MRI is a constantly expanding field, a unique non-invasive tool with immense potential in evaluating the in vivo evolution of the neurodegenerative ALS process, both structurally and functionally, with high hopes for the future. Abbreviations: ALS - amyotrophic lateral sclerosis, UMN - upper motor neuron, LMN - lower motor neuron, EMG - electromyography, CST - cortico-spinal tract, FLAIR - fluid-attenuated inversion recovery, MND - motor neuron disease, DTI - Diffusion tensor imaging, FA - fractional anisotropy, MD - mean diffusivity, ihMTR - inhomogeneous magnetization transfer, fMRI - functional MRI.
 ...
PMID:A review of cervical spine MRI in ALS patients. 3014 Mar 18

Upper motor neuron [UMN] and lower motor neuron [LMN] dysfunction, in the absence of sensory features, is a pathognomonic feature of amyotrophic lateral sclerosis [ALS]. Although the precise mechanisms have yet to be elucidated, one leading hypothesis is that UMN precede LMN dysfunction, which is induced by anterograde glutamatergic excitotoxicity. Transcranial magnetic stimulation (TMS) is a neurophysiological tool that provides a non-invasive and painless assessment of cortical function. Threshold tracking methodologies have been recently adopted for TMS, whereby changes in threshold rather than motor evoked potential (MEP) amplitude serve as outcome measures. This technique is reliable and provides a rapid assessment of cortical function in ALS. Utilisng the threshold tracking TMS technique, cortical hyperexcitability was demonstrated as an early feature in sporadic ALS preceding the onset of LMN dysfunction and possibly contributing to disease spread. Separately, cortical hyperexcitability was reported to precede the clinical onset of familial ALS. Of further relevance, the threshold tracking TMS technique was proven to reliably distinguish ALS from mimicking disorders, even in the presence of a comparable degree of LMN dysfunction, suggesting a diagnostic utility of TMS. Taken in total, threshold tracking TMS has provided support for a cortical involvement at the earliest detectable stages of ALS, underscoring the utility of the technique for probing the underlying pathophysiology. The present review will discuss the physiological processes underlying TMS parameters, while further evaluating the pathophysiological and diagnostic utility of threshold tracking TMS in ALS.
 ...
PMID:Utility of threshold tracking transcranial magnetic stimulation in ALS. 3056 Feb 20

The clinical diagnosis of amyotrophic lateral sclerosis (ALS) relies on determination of progressive dysfunction of both cortical as well as spinal and bulbar motor neurons. However, the variable mix of upper and lower motor neuron signs result in the clinical heterogeneity of patients with ALS, resulting frequently in delay of diagnosis as well as difficulty in monitoring disease progression and treatment outcomes particularly in a clinical trial setting. As such, the present review provides an overview of recently developed novel non-invasive electrophysiological techniques that may serve as biomarkers to assess UMN and LMN dysfunction in ALS patients.
 ...
PMID:Functional Biomarkers for Amyotrophic Lateral Sclerosis. 3066 29

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunctions resulting from the loss of upper (UMNs) and lower (LMNs) motor neurons. While ALS symptoms are coincidental with pathological changes in LMNs and UMNs, the causal relationship between the two is unclear. For example, research on the extra-motor symptoms associated with this condition suggests that an imbalance of metals, including copper, zinc, iron, and manganese, is initially induced in the sensory ganglia due to a malfunction of metal binding proteins and transporters. It is proposed that the resultant metal dyshomeostasis may promote mitochondrial dysfunction in the satellite glial cells of these sensory ganglia, causing sensory neuron disturbances and sensory symptoms. Sensory neuron hyperactivation can result in LMN impairments, while metal dyshomeostasis in spinal cord and brain stem parenchyma induces mitochondrial dysfunction in LMNs and UMNs. These events could prompt intracellular calcium dyshomeostasis, pathological TDP-43 formation, and reactive microglia with neuroinflammation, which in turn activate the apoptosis signaling pathways within the LMNs and UMNs. Our model suggests that the degeneration of LMNs and UMNs is incidental to the metal-induced changes in the spinal cord and brain stem. Over time psychiatric symptoms may appear as the metal dyshomeostasis and mitochondrial dysfunction affect other brain regions, including the reticular formation, hippocampus, and prefrontal cortex. It is proposed that metal dyshomeostasis in combination with mitochondrial dysfunction could be the underlying mechanism responsible for the initiation and progression of the pathological changes associated with both the motor and extra-motor symptoms of ALS.
 ...
PMID:A novel hypothesis on metal dyshomeostasis and mitochondrial dysfunction in amyotrophic lateral sclerosis: Potential pathogenetic mechanism and therapeutic implications. 3322 Feb 80


<< Previous 1 2